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Willem, M.* ; Tahirovic, S.* ; Busche, M.A.* ; Ovsepian, S.V.* ; Chafai, M.* ; Kootar, S.* ; Hornburg, D.* ; Evans, L.D.* ; Moore, S.* ; Daria, A.* ; Hampel, H.* ; Müller, V.* ; Giudici, C.* ; Nuscher, B.* ; Wenninger-Weinzierl, A.* ; Kremmer, E. ; Heneka, M.T.* ; Thal, D.R.* ; Giedraitis, V.* ; Lannfelt, L.* ; Müller, U.* ; Livesey, F.J.* ; Meissner, F.* ; Herms, J.* ; Konnerth, A.* ; Marie, H.* ; Haass, C.*

η-secretase processing of APP inhibits neuronal activity in the hippocampus.

Nature 526, 443-447 (2015)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Journal Nature
Quellenangaben Volume: 526, Issue: 7573, Pages: 443-447 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)